Autoimmune diseases are a group of more than 80 distinct diseases that emerge when a host's immune response fails to distinguish foreign antigens from self molecules (autoantigens), thereby eliciting an aberrant immune response. The causes of autoimmune diseases are still obscure, however they are thought to be caused by a combination of genetic and environmental factors.
Immuno-inflammatory disorders like multiple sclerosis, psoriasis and rheumatoid arthritis share a common pathogenic principle. Their pathogenesis is characterized by autoreactive memory T cells mediating chronic inflammatory processes upon stimulation. In particular, repeated antigenic challenge, usually occurring in autoimmune diseases, causes long-lived central memory cells (TCM), which like naïve cells, home to lymph nodes to encounter their cognate antigen, to differentiate into short-lived effector memory cells (TEM) that do not need to home to lymph nodes for antigen-induced activation. Activated TEM cells change into TEM effectors, which migrate rapidly to sites of inflammation where they produce large amounts of proinflammatory cytokines. CD8+ TEM cells further produce high amounts of perform and are thus highly destructive.
The current treatments for autoimmune diseases include the systemic use of anti-inflammatory drugs and potent immunosuppressive and immunomodulatory agents. However, these drugs cause numerous adverse side effects including e.g. suppression of the immune system as a whole, with the risk of infection and neoplasia. Furthermore, in some patients said drugs are unable to induce clinically significant remissions.
The voltage-gated Kv1.3 K+ channel is one of 76 potassium channels in the human genome and has been found to be present in human T lymphocytes. All human T cells express the Kv1.3 channel as well as the calcium-activated KCa3.1, which together provide the counter-balancing potassium efflux for the calcium influx that is necessary for T cell activation and proliferation. The number of channels expressed by a given cell depends on its state of activation and differentiation. Antigen or mitogen stimulated CD4+ and CD8+ TEM cells exhibit an approximately 4- to 5-fold increased expression of Kv1.3, while human naïve or TCM cells up-regulate the calcium-activated KCa3.1 channel to regulate membrane potential and Ca2+ signaling in the activated state.
In view of this differential overexpression in TEM cells, the Kv1.3 channel constitutes a promising new TEM-cell-specific therapeutic target for the treatment of autoimmune diseases, whose pathogenesis involves autoreactive TEM cells such as e.g. multiple sclerosis, rheumatoid arthritis, psoriasis and type-1 diabetes, but also for other chronic inflammatory diseases, such as e.g. parodontitits.
Furthermore, there is indication that Kv1.3 channels play a role in the regulation of body weight. The Kv1.3 channel thus also constitutes a promising target for the treatment of obesity.
Therefore, there is an ongoing need for Kv1.3 channel specific therapeutic compounds that exhibit a strong and specific interaction with the Kv1.3 channel and are capable of blocking or reducing its activity.